Method for producing solid dosing forms

ABSTRACT

A process for producing solid dosage forms by forming a plastic mixture of at least one polymeric binder, at least one active ingredient and, where appropriate, conventional additives, and shaping the plastic mixture to the solid dosage forms using a mold, wherein an agent which modifies the surface properties is applied in finely divided form to the surface of the plastic, mixture during the shaping is described. The agent which modifies the surface properties is preferably a surfactant, a lipophilic compound, an antioxidant, a coloring agent or an agent with antistatic effect and/or lubricant effect.

The present invention relates to a process for producing solid dosageforms by forming a plastic mixture of at least one polymeric binder, atleast one active ingredient and, where appropriate, conventionaladditives, and shaping the plastic mixture to the solid dosage formsusing a mold.

The production of solid dosage forms by extrusion and subsequentcalendering of an active ingredient-containing melt is disclosed, forexample in DE-A-17 66 546 and U.S. Pat. No. 4,880,585. This process isbased on the embedding of an active ingedient in a melt of a carrier,for example fatty substances or water-soluble, thermoplastic polymers.The melt is produced by melting the mixture of active ingredient,polymer and, where appropriate, other ancillary substances, for examplein an extruder, and shaping as melt in a subsequent shaping calender totablets, which harden by cooling.

Solid dosage forms ordinarily contain not only the carrier substance butalso one or more ancillary substances. On the hand, these ancillarysubstances are often indispensable in order to control the release ofthe active ingredient, to prevent decomposition of the active ingredientdue to light and/or oxidation, to mask an unpleasant taste of the activeingredient, to make the dosage forms colored for easier identificationetc. On the other hand, ancillary substances are usually necessary inorder to ensure satisfactory industrial processability of the dosageforms during production, during subsequent processing steps etc.

The required ancillary substances are usually incorporated into thetablet composition, i.e. in the finished dosage forms, they areuniformly distributed in the volume of the dosage forms. However, mostof the ancillary substances employed display their effect only on thesurface of the dosage forms. This means that only the portion of theancillary substances located in the outermost surface layer and a fewmicrometers below that contributes to the required effect. In order tohave a sufficient concentration at the surface, it is thereforenecessary for these ancillary substances to be incorporated inrelatively high concentration into the tablet composition. Most of theancillary substance in the tablet volume remains without effect, whichmakes the production of the tablets unnecessarily costly. There may alsobe unwanted interactions of the ancillary substance with the activeingredient or with the substances forming the matrix.

In addition, the freedom of formulating the tablet composition isrestricted because it is possible to use only active ingredients andancillary substances which are compatible with one another.

On the other hand, it is known to coat tablets in the last step ofmanufacture with a thin layer of, for example, water-soluble polymers.Film-coated tablets are produced in this way. If a coating was requiredover the tablets produced by melt calendering, it was necessary to applythis coating in a separate step after cooling of the tablets. This tookplace in a conventional way, for example by spraying on in rotatingdrums, by dipcoating or in a fluidized bed etc. The conventionalprocesses for applying coating layers all require a comparatively largeenergy input because the solvents used in the spray solutions must beremoved again rapidly after spraying onto the tablets. In addition, acoating process usually takes several hours because the spraying ratecannot be set as high as desired.

WO 96/19963 describes a process for producing coated tablets by meltcalendering, in which the active ingredient-containing melt isintroduced between two sheets of the coating material into the calendermolding rolls. This process is, however, suitable only for ancillarysubstances which can easily be produced in the form of a sheet.

DE-A-44 46 467 describes a process for producing lenticular tablets bymelt calendering. It is pointed out in this publication that moldingrolls provided with a release agent can be used. An example of asuitable release agent is a silicone paint. This suggests that themolding rolls are lined only once with the release agent and there is notransfer of the release agent from the molding rolls to the mixture tobe tableted.

It is an object of the present invention to provide a process forproducing solid dosage forms by melt extrusion, in which a modificationof the surface properties of the solid dosage forms is possible in asimple and cost- and material-saving manner.

We have found that this object is achieved by applying an agent whichmodifies the surface properties in finely divided form to the surface ofthe plastic mixture during the shaping. The outer surface of the plasticmixture which is created by the shaping to solid dosage forms is in thisway provided with an agent which modifies the surface properties.

The present invention therefore relates to a process for producing soliddosage forms by forming a plastic mixture of at least one polymericbinder, at least one active ingredient and, where appropriate,conventional additives, and shaping the plastic mixture to the soliddosage forms using a mold, wherein an agent which modifies the surfaceproperties is applied in finely divided form to the surface of theplastic mixture during the shaping. The process according to theinvention is preferably carried out continuously. It is essential forthe process according to the invention that a continuous supply of agentwhich modifies the surface properties is ensured. It is also importantthat the agent which modifies the surface properties is applied at atime at which the plastic mixture has not yet completely solidified.

The term “shaping” may comprise the steps of preforming and definitiveshaping. “Preforming” means every procedure in which the ratio of thesurface area to the volume of the plastic mixture already substantiallyapproximates to that of the finished dosage form. The preformed plasticmixture is preferably exposed to negligible shear forces during thedefinitive shaping, so that surface elements are not mixed into theinterior.

Preforming is regarded as being, for example, the extrusion of theplastic mixture to give a ribbon or a sheet. It is thus possible withinthe scope of the present invention to apply the agent which modifies thesurface properties to the surface of the preformed plastic mixture, e.g.of the ribbon or sheet, which is subsequently subjected to thedefinitive shaping.

The process according to the invention makes a considerable saving ofancillary substances possible without losses of efficacy because thedosage forms obtained according to the invention contain the ancillarysubstances predominantly or exclusively on their surface, while theconcentration of ancillary substances over the volume of the dosageforms can be reduced, or the composition to be tableted can be kept freeof ancillary substances.

The agent which modifies the surface properties is applied in finelydivided form. This means that the agent is in powdered or liquid formand not in compact form, e.g. as sheet. The agent which modifies thesurface properties can be applied in the form of a powder, a solution, asuspension, emulsion or dispersion. Where carrier liquids are requiredto produce a solution, suspension, emulsion or dispersion, these can bechosen to be volatile or else involatile.

Agents which modify the surface properties mean for the purpose of theinvention all pharmaceutically suitable ancillary substances which alterthe physical and/or chemical properties of the dosage forms which arecaused wholly or partly by surface effects, e.g. color, pourability,separation characteristics, surface slip, sievability, permeability forvapors and/or gases, transparency, lipophilicity/hydrophilicity, redoxpotential, surface tension etc. They comprise ancillary substancesnormally incorporated into the tablet composition, and those whose useis made possible by the present invention for the first time.

Depending on the nature of the agent used to modify the surfaceproperties, it is embedded or partly dissolved in the surface of theplastic mixture. In each case, the aim is permanent attachment of theagent which modifies the surface properties to the resulting dosageforms.

In a preferred embodiment of the invention, the agent which modifies thesurface properties is a surfactant, preferably with an HLB of more than10. Surfactants are able to increase the wettability of the dosage formsand thus improve the dissolving properties. In addition, surfactants mayimprove the release properties of the dosage forms. Suitable surfactantswhich may be mentioned are: fatty acid monoesters of polyhydroxyethylenesorbitan such as polyethylene glycol 20 sorbitan monolaurate (HLB 16.7),polyethylene glycol 20 sorbitan monostearate (HLB 14.9), polyethyleneglycol 20 sorbitan monooleate (HLB 15.0), polyhydroxyethylene fattyalcohol ethers or fatty acid esters, such as polyhydroxyethylenecetylstearyl ether (Cremophor®O, HLB 16.1), polyhydroxyethylene 23lauryl ether (HLB 16.9), polyhydroxyethylene 8 stearate (HLB 11.1),polyhydroxyethylene 40 stearate (HLB 16.8), polyhydroxyethylene 100stearate (HLB 18.8), ethylene oxide propylene oxide block copolymers(Pluronic®), ethoxylated triglycerides, e.g. polyethoxylated castor oil40 (Cremophor®EL; HLB 12-14), polyethoxylated hydrogenated castor oil 40(Cremophor®RH; HLB 14-16).

In another preferred embodiment of the invention, the agent whichmodifies the surface properties is a lipophilic compound which ispreferably selected from glycerides, waxes, fatty acids, fatty alcohols,paraffins, silicones and phosphatides. The use of a lipophilic compoundfor the purpose of the present invention allows the surface of thedosage forms to be made lipophilic. It is possible in this way, forexample, to delay the release of the active ingredient and thus theonset of action of a drug product. It is additionally possible to reducethe adhesion of dosage forms stored as loose material. The penetrationof water or water vapor or other constituents of the air into the dosageform can be reduced or suppressed, which has advantageous effects on thestorage stability of the dosage forms. Examples of lipophilic compoundswhich are suitable for the purpose of the invention are, inter alia,hydrocarbons such as liquid and solid paraffin, petrolatum; fattyalcohols such as cetyl alcohol, stearyl alcohol, cetostearyl alcohol(Lanette®O), 2-octyldodecanol (Eutanol®G); fatty acids such as stearicacid; salts of fatty acids such as magnesium stearate, calcium stearate;glycerides such as arachis oil, olive oil, sesame oil, hydrogenatedarachis oil, hydrogenated cottonseed oil, hydrogenated castor oil,semisynthetic and synthetic glycerides; waxes such as beeswax, carnaubawax, cetyl palmitate, wool wax (Lanolin®), isopropyl myristate,isopropyl stearate, Cetiol®V, ethyl oleate; phosphatides such as egglecithin or soybean lecithin.

In another preferred embodiment of the invention, the agent whichmodifies the surface properties is an antioxidant which is preferablyselected from ascorbic acid, ascorbyl palmitate, butylatedhydroxytoluene, butylated hydroxyanisole, propyl gallate andtocopherols. Wax-like antioxidants, in particular with a melting pointof less than 100° C., are preferred. The use of an antioxidant preventsoxidation-sensitive ingredients of the dosage forms being oxidized byentry of atmospheric oxygen during storage.

In another preferred embodiment of the invention, the agent whichmodifies the surface properties is a coloring agent, e.g. a soluble dyeor else an inorganic or organic pigment. Suitable coloring agents whichmay be mentioned are iron oxides, talc, calcium carbonate, titaniumdioxide, for example organic dyes laked with alumina, such aserythrosine, orange yellow S, tartrazine, indigotine, Ponceau 4 R,quinoline yellow, patent blue V; azo dyes etc. It has emerged that theuse of insoluble colored pigments such as iron oxides is associated withan improvement in the release properties.

In another preferred embodiment of the invention, the agent whichmodifies the surface properties is an agent with antistatic effectand/or lubricant effect. Antistatic agents improve the pourability, theseparation characteristics, the surface slip and the sievability of thedosage forms. Suitable antistatic agents which may be mentioned are,inter alia, glycol, glycerol, Aerosil, polyethylene glycol esters,polyethylene glycol, dicalcium phosphate and lactose. Lubricants areused to improve the release of the dosage forms from the mold. Suitablelubricants which may be mentioned are, inter alia, magnesium stearate,calcium behenate, sodium stearylfumarate, polyethylene glycols,phosphatidylcholine derivatives, stearic acid, talc, Aerosil, calciumstearate, glycerol esters, hydrogenated cottonseed oil, hydrogenatedcastor oil and rice starch.

It is self-evident that an agent which modifies the surface propertiesmay be subsumed simultaneously by more than one of the abovementionedpreferred embodiments. On the other hand, it is possible for agentswhich modify surface properties from two or more of the abovementionedembodiments to be combined and applied simultaneously or successively.

It is generally preferred for the agent which modifies the surfaceproperties or the mixture of agents which modify the surface propertiesto comprise about 0.01 to 1.0% by weight, preferably about 0.01 to 0.5%by weight, in particular about 0.01 to about 0.3% by weight, based onthe total weight of the resulting solid dosage form.

Dosage forms mean in the present case all forms suitable for use as drugproducts, crop treatment products, animal food products and human foodproducts and for delivering fragrances and perfume oils. These include,for example, tablets of every shape, pellets, granules, but also largerforms such as cubes, blocks (bricks) or cylindrical forms, which can beused in particular as animal food or human food products.

The plastic mixture generally comprises:

a) 0.1 to 90% by weight, in particular 0.1 to 60% by weight (based onthe total weight of the dosage form) of an active ingredient,

b) 10 to 99.9% by weight, in particular 40 to 99.9% by weight, of apolymeric binder, and

c) where appropriate additives.

The binder should preferably be soluble or swellable in a physiologicalenvironment. Examples of suitable binders are polyvinylpyrrolidone(PVP), copolymers of N-vinylpyrrolidone (NVP) and vinyl esters, inparticular vinyl acetate, copolymers of vinyl acetate and crotonic acid,partially hydrolyzed polyvinyl acetate, polyvinyl alcohol,poly(hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylates),polyacrylates and polymethacrylates (Eudragit types), copolymers ofmethyl methacrylate and acrylic acid, cellulose esters, celluloseethers, in particular methylcellulose and ethylcellulose, hydroxyalkylcelluloses, in particular hydroxypropylcellulose,hydroxyalkylalkylcelluloses, in particular hydroxypropylethylcellulose,cellulose phthalates, in particular cellulose acetate phthalate andhydroxypropylmethylcellulose phthalate, starch, starch derivatives, e.g.maltodextrins, sugar alcohols, such as mannitol or palatinose andmannans, in particular galactomannans. The K values (method of H.Fikentscher, Cellulose-Chemie 13, 1932, 58-64 and 71-74) of the polymersare in the range from 10 to 100, preferably 12 to 70, in particular 12to 35, and for PVP preferably 12 to 35, in particular 12 to 17.

The polymeric binder must soften or melt in the complete mixture of allthe components in the range from 50 to 180, preferably 60 to 130° C., sothat the composition can be extruded. The glass transition temperatureof the mixture must therefore be below 180° C., preferably below 130° C.If necessary, it is reduced by conventional pharmacologicallyacceptable, plasticizing ancillary substances such as long-chainalcohols, ethylene glycol, propylene glycol, glycerol,trimethylolpropane, triethylene glycol, sugar alcohols, e.g.butanediols, pentanols, and pentaerythritol or hexanols, polyethyleneglycols, polypropylene glycols, polyethylene/propylene glycols,silicones, aromatic carboxylic esters (e.g. dialkyl phthalates,trimellitic esters, benzoic esters, terephthalic esters) or aliphaticdicarboxylic esters (e.g. dialkyl adipates, sebacic esters, azelaicesters, citric and tartaric esters), fatty acid esters such as glycerolmono-, glycerol di- or glycerol triacetate or sodium diethylsulfosuccinate. The concentration of plasticizer is generally 0.5 to 15%by weight, preferably 0.5 to 5% by weight, based on the total weight ofthe composition. The mixture preferably comprises no plasticizer. Activepharmaceutical ingredients for the purpose of the invention mean allsubstances with a pharmaceutical effect and minimal side effects as longas they do not decompose under the processing conditions. The amount ofactive ingredient per dose unit and the concentration may vary withinwide limits depending on the activity and release rate. The onlycondition is that they suffice to achieve the desired effect. Thus, theactive ingredient concentration may be in the range from 0.1 to 95,preferably from 20 to 80, in particular 30 to 70, % by weight. It isalso possible to employ combinations of active ingredients, e.g.ibuprofen/caffeine. Active ingredients for the purpose of the inventionare also vitamins and minerals, and crop treatment agents andinsecticides. The vitamins include the vitamins of the A group, the Bgroup, meaning not only B₁, B₂, B₆ and B₁₂ and nicotinic acid andnicotinamide but also compounds with vitamin B properties such asadenine, choline, pantothenic acid, biotin, adenylic acid, folic acid,orotic acid, pangamic acid, carnitine, p-aminobenzoic acid, myo-inositoland lipoic acid, and vitamin C, vitamins of the D group, E group, Fgroup, H group, I and J groups, K group and P group. Active ingredientsfor the purpose of the invention also include therapeutic peptides.

Active ingredients mean for the purpose of the invention all substanceswith a physiological action as long as they do not decompose under theprocessing conditions. They are, in particular, active pharmaceuticalingredients (for humans and animals), active ingredients for croptreatment, insecticides, active ingredients for animal food and humanfood products, fragrances and perfume oils. The amount of activeingredient per dose unit and the concentration may vary within widelimits depending on the activity and release rate. The only condition isthat they suffice to achieve the desired effect. Thus, the activeingredient concentration may be in the range from 0.1 to 95, preferablyfrom 20 to 80, in particular 30 to 70, % by weight. It is also possibleto employ combinations of active ingredients. Active ingredients for thepurpose of the invention are also vitamins and minerals. The vitaminsinclude the vitamins of the A group, the B group, meaning not only B₁,B₂, B₆ and B₁₂ and nicotinic acid and nicotinamide but also compoundswith vitamin B properties such as adenine, choline, pantothenic acid,biotin, adenylic acid, folic acid, orotic acid, pangamic acid,carnitine, p-aminobenzoic acid, myo-inositol and lipoic acid, andvitamin C, vitamins of the D group, E group, F group, H group, I and Jgroups, K group and P group. Active ingredients for the purpose of theinvention also include therapeutic peptides. Crop treatment agentsinclude, for example, vinclozolin, epoxiconazole and quinmerac.

The process according to the invention is suitable, for example, forprocessing the following active ingredients:

acebutolol, acetylcysteine, acetylsalicylic acid, acyclovir, alprazolam,alfacalcidol, allantoin, allopurinol, ambroxol, amikacin, amiloride,aminoacetic acid, amiodarone, amitriptyline, amlodipine, amoxicillin,ampicillin, ascorbic acid, aspartame, astemizole, atenolol,beclomethasone, benserazide, benzalkonium-hydrochloride, benzocaine,benzoic acid, betamethasone, bezafibrate, biotin, biperiden, bisoprolol,bromazepam, bromhexine, bromocriptine, budesonide, bufexamac,buflomedil, buspirone, caffeine, camphor, captopril, carbamazepine,carbidopa, carboplatin, cefachlor, cefalexin, cefadroxil, cefazolin,cefixime, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, selegiline,chloramphenicol, chlorhexidine, chlorpheniramine, chlortalidone,choline, cyclosporin, cilastatin, cimetidine, ciprofloxacin, cisapride,cisplatin, clarithromycin, clavulanic acid, clomipramine, clonazepam,clonidine, clotrimazole, codeine, cholestyramine, cromoglycic acid,cyanocobalamin, cyproterone, desogestrel, dexamethasone, dexpanthenol,dextromethorphan, dextropropoxiphene, diazepam, diclofenac, digoxin,dihydrocodeine, dihydroergotamine, dihydroergotoxin, diltiazem,diphenhydramine, dipyridamole, dipyrone, disopyramide, domperidone,dopamine, doxycycline, enalapril, ephedrine, epinephrine,ergocalciferol, ergotamine, erythromycin, estradiol, ethinylestradiol,etoposide, Eucalyptus globulus, famotidine, felodipine, fenofibrate,fenoterol, fentanyl, flavin mononucleotide, fluconazole, flunarizine,fluorouracil, fluoxetine, flurbiprofen, furosemide, gallopamil,gemfibrozil, gentamicin, Ginkgo biloba, glibenclamide, glipizide,clozapine, Glycyrrhiza glabra, griseofulvin, guaifenesin, haloperidol,heparin, hyaluronic acid , hydrochlorothiazide, hydrocodone,hydrocortisone, hydromorphone, ipratropium hydroxide, ibuprofen,imipenem, indomethacin, iohexol, iopamidol, isosorbide dinitrate,isosorbide mononitrate, isotretinoin, ketotifen, ketoconazole,ketoprofen, ketorolac, labetalol, lactulose, lecithin, levocarnitine,levodopa, levoglutamide, levonorgestrel, levothyroxine, lidocaine,lipase, imipramine, lisinopril, loperamide, lorazepam, lovastatin,medroxyprogesterone, menthol, methotrexate, methyldopa,methylprednisolone, metoclopramide, metoprolol, miconazole, midazolam,minocycline, minoxidil, misoprostol, morphine, multivitamin mixtures andcombinations and mineral salts, N-methylephedrine, naftidrofuryl,naproxen, neomycin, nicardipine, nicergoline, nicotinamide, nicotine,nicotinic acid, nifedipine, nimodipine, nitrazepam, nitrendipine,nizatidine, norethisterone, norfloxacin, norgestrel, nortriptyline,nystatin, ofloxacin, omeprazole, ondansetron, pancreatin, panthenol,pantothenic acid, paracetamol, penicillin G, penicillin V,phenobarbital, pentoxifylline, phenoxymethylpenicillin, phenylephrine,phenylpropanolamine, phenytoin, piroxicam, polymyxin B, povidone-iodine,pravastatin, prazepam, prazosin, prednisolone, prednisone,bromocriptine, propafenone, propranolol, proxyphylline, pseudoephedrine,pyridoxine, quinidine, ramipril, ranitidine, reserpine, retinol,riboflavin, rifampicin, rutoside, saccharin, salbutamol, salcatonin,salicylic acid, simvastatin, somatropin, sotalol, spironolactone,sucralfate, sulbactam, sulfamethoxazole, sulfasalazine, sulpiride,tamoxifen, tegafur, teprenone, terazosin, terbutaline, terfenadine,tetracycline, theophylline, thiamine, ticlopidine, timolol, tranexamicacid, tretinoin, triamcinolone acetonide, triamterene, trimethoprim,troxerutin, uracil, valproic acid, vancomycin, verapamil, vitamin E,folinic acid, zidovudine.

Preferred active ingredients are ibuprofen (as racemate, enantiomer orenriched enantiomer), ketoprofen, flurbiprofen, acetylsalicylic acid,verapamil, paracetamol, nifedipine or captopril.

Besides the obligatorily present agent which modifies the surfaceproperties, the dosage forms obtained according to the invention maycontain in the matrix conventional pharmaceutical ancillary substances,the total amount of which may be up to 100% by weight, based on thepolymeric binder. Conventional pharmaceutical ancillary substances are,for example, extenders and bulking agents such as magnesium oxide,aluminum oxide, titanium oxide, stearic acid or salts thereof, e.g. themagnesium or calcium salt, methylcellulose, sodiumcarboxymethylcellulose, talc, sucrose, lactose, cereal or corn starch,potato flour, polyvinyl alcohol, in particular in a concentration offrom 0.02 to 50, preferably 0.20 to 20, % by weight, based on the totalweight of the mixture;

Lubricants such as aluminum and calcium stearates, talc and silicones,in a concentration of from 0.1 to 5, preferably 0.1 to 3, % by weightbased on the total weight of the mixture;

Flow regulators such as animal or vegetable fats, in particular inhydrogenated form and those which are solid at room temperature. Thesefats preferably have a melting point of 50° C. or above. Triglyceridesof C₁₂, C₁₄, C₁₆ and C₁₈ fatty acids are preferred. It is also possibleto use waxes such as carnauba wax. These fats and waxes may be admixedadvantageously alone or together with mono- and/or diglycerides orphosphatides, in particular lecithin. The mono- and diglycerides arepreferably derived from the abovementioned fatty acid types. The totalamount of fats, waxes, mono-, diglycerides and/or lecithins is 0.1 to30, preferably 0.1 to 5, % by weight, based on the total weight of thecomposition for the particular layer;

Dyes such as azo dyes, organic or inorganic pigments or dyes of naturalorigin, with preference for inorganic pigments in a concentration offrom 0.001 to 10, preferably 0.5 to 3, % by weight, based on the totalweight of the mixture;

Stabilizers such as antioxidants, light stabilizers, hydroperoxidedestroyers, radical scavengers, stabilizers against microbial attack.

It is also possible to add wetting agents, preservatives, disintegrants,adsorbents, mold release agents and blowing agents (cf., for example, H.Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart1978).

Ancillary substances for the purpose of the invention also meanssubstances for producing a solid solution of the active ingredient.Examples of these ancillary substances are pentaerythritol andpentaerythritol tetraacetate, polymers such as polyethylene oxides andpolypropylene oxides and their block copolymers (poloxamers),phosphatides such as lecithin, homo- and copolymers of vinylpyrrolidone,surfactants such as polyoxyethylene 40 stearate and citric and succinicacids, bile acids, sterols and others, as indicated, for example, by J.L. Ford, Pharm. Acta Helv. 61, 69-88 (1986).

Ancillary substances are also regarded as being bases and acids added tocontrol the solubility of an active ingredient (see, for example, K.Thoma et al., Pharm. Ind. 51, 98-101 (1989)).

The only precondition for the suitability of ancillary substances isadequate thermal stability.

To produce the solid dosage forms, a plastic mixture of the components(melt) is prepared and is then subjected to a shaping step. The mixingof the components and the formation of the melt can take place invarious ways. The mixing can take place before, during and/or after theformation of the melt. For example, the components can be first mixedand then melted or be mixed and melted simultaneously. The plasticmixture is often then homogenized in order to disperse the activeingredient thoroughly.

However, it has proven preferable, especially when sensitive activeingredients are used, first to melt the polymeric binder and, whereappropriate, make a premix with conventional pharmaceutical additives,and then to mix in (homogenize) the sensitive active ingredient(s) inthe plastic phase in intensive mixers with very short residence times.The active ingredient(s) can for this purpose be employed in solid formor in solution or dispersion.

The components are generally used as such in the production process.They can, however, also be used in liquid form, i.e in solution,suspension or dispersion.

Suitable solvents for the liquid form of the components are primarilywater or a water-miscible organic solvent or a mixture thereof withwater. However, it is also possible to use organic solvents which areimmiscible or miscible with water. Suitable water-miscible solvents are,in particular, acetone, C₁-C₄-alkanols such as ethanol, isopropanol orn-propanol, polyols such as ethylene glycol, glycerol and polyethyleneglycols. Suitable water-immiscible solvents are alkanes such as pentaneor hexane, esters such as ethyl acetate or butyl acetate, chlorinatedhydrocarbons such as methylene chlorie, and aromatic hydrocarbons suchas toluene and xylene. Another solvent which can be used is liquid CO₂.

The solvent used in the individual case depends on the component to betaken up and the properties thereof. For example, active pharmaceuticalingredients are frequently used in the form of a salt which is, ingeneral, soluble in water. Water-soluble active ingredients cantherefore be employed as aqueous solution or, preferably, be taken up inthe aqueous solution or dispersion of the binder. A correspondingstatement applies to active ingredients which are soluble in one of thesolvents mentioned, if the liquid form of the components used is basedon an organic solvent.

It is possible where appropriate to replace melting by dissolving,suspending or dispersing in the abovementioned solvents, if desiredand/or necessary with the addition of suitable ancillary substances suchas emulsifiers. The solvent is then generally removed to form the meltin a suitable apparatus, e.g. an extruder. This will be comprised by theterm mixing hereinafter.

The melting and/or mixing takes place in an apparatus customary for thispurpose. Particularly suitable ones are extruders or containers whichcan be heated where appropriate and have an agitator, e.g. kneaders(like those of the type to be mentioned below).

A particularly suitable mixing apparatus is one employed for mixing inplastics technology. Suitable apparatuses are described, for example, in“Mischen beim Herstellen und Verarbeiten von Kunststoffen”, H. Pahl,VDI-Verlag, 1986. Particularly suitable mixing apparatus are extrudersand dynamic and static mixers, and stirred vessels, single-shaftstirrers with stripper mechanisms, especially paste mixers, multishaftstirrers, especially PDSM mixers, solids mixers and, preferably,mixer/kneader reactors (e.g. ORP, CRP, AP, DTB supplied by List orReactotherm supplied by Krauss-Maffei or Ko-Kneader supplied by Buss),trough mixers and internal mixers or rotor/stator systems (e.g. Dispaxsupplied by IKA).

In the case of sensitive active ingredients it is preferable first forthe polymeric binder to be melted in an extruder and then for the activeingredient to be admixed in a mixer/kneader reactor. On the other hand,with less sensitive active ingredients, a rotor/stator system can beemployed for vigorously dispersing the active ingredient.

The mixing apparatus is charged continuously or batchwise, depending onits design, in a conventional way. Powdered components can be introducedin a free feed, e.g. via a weigh feeder. Plastic compositions can be fedin directly from an extruder or via a gear pump, which is particularlyadvantageous if the viscosities and pressures are high. Liquid media canbe metered in via a suitable pump unit.

The mixture obtained by mixing and/or melting the binder, the activeingredient and, where appropriate, the additive or additives ranges frompasty to viscous (plastic) or fluid and is therefore extrudable. Theglass transition temperature of the mixture is below the decompositiontemperature of all the components present in the mixture. The bindershould preferably be soluble or swellable in a physiological medium.

The steps of mixing and melting in the process can be carried out in thesame apparatus or in two or more separately operating apparatuses. Thepreparation of a premix can take place in one of the conventional mixingapparatuses described above. A premix of this type can then be feddirectly, for example into an extruder and subsequently extruded, whereappropriate with the addition of other components.

It is possible in the process according to the invention to employ asextruders single screw machines, intermeshing screw machines or elsemultiscrew extruders, especially twin screw extruders, corotating orcounterrotating and, where necessary, equipped with kneading disks. Ifit is necessary in the extrusion to evaporate a solvent, the extrudersare generally equipped with an evaporating section. Particularlypreferred extruders are those of the ZKS series from Werner &Pfleiderer.

The resulting mixture is preferably solvent-free, i.e. it containsneither water nor an organic solvent. The thermoformable extrudate ofthe plastic mixture is subjected to a definitive shaping to give thesolid dosage forms using a mold. It is possible in this way to produce alarge number of shapes depending on the mold and manner of shaping. Forexample, it is possible on use of an extruder to shape the extrudatebetween a belt and a roll, between two belts or between two rolls, asdescribed in EP-A-358 105. It is particularly preferred to use a moldwith two counterrotating molding rolls, of which at least one hasdepressions to receive and shape the plastic mixture. This type ofshaping is normally referred to as calendering and is described, forexample, in EP-A-240 904. Further shapes can be obtained by extrusionand hot or cold cut of the extrudate, for example small-particle anduniformly shaped granules. Hot-cut pelletization usually results inlenticular dosage forms (tablets) with a diameter of from 1 to 10 mm,whereas cold-cut pelletization normally results in cylindrical productswith a length to diameter ratio of from 1 to 10 mm and a diameter offrom 0.5 to 10 mm. It is possible in this way to produce, for example,oblong tablets, coated tablets, pastilles and pellets.

The application of the agent which modifies the surface properties tothe surface of the plastic mixture can take place in a variety of ways.Thus, for example, the extruded plastic mixture can be passed through abath or bed of the agent which modifies the surface properties. Theagent which modifies the surface properties can be sprayed, painted,brushed or blown onto the preformed plastic mixture, for example usingsingle-component or multicomponent nozzle systems. Transfer rolls can beused.

A particularly preferred process is one in which the agent whichmodifies the surface properties is initially applied in finely dividedform to the surfaces of the mold which come into contact with theplastic mixture. Every contact of the surfaces of the mold with theplastic mixture is followed by a new application of the agent whichmodifies the surface properties. It is thus possible on use of a moldwith two counterrotating molding rolls, at least one of which hasdepressions to receive and shape the plastic mixture (molding calender),for the molding rolls to be provided with the agent which modifies thesurface properties. As soon as the plastic mixture enters thedepressions, the soft, occasionally tacky surface of the plastic mixturetakes up the agent which modifies the surface properties, and apermanent attachment between the two is brought about. Application ofthe agent which modifies the surface properties to the molding rolls cantake place, for example, by the underside of the rolls passing through abath, or by the agent being sprayed on or applied using brushes, e.g.using a circular brush with tubing connection.

Particularly good results have been obtained using the following agentswhich modify the surface properties, in the stated concentration (% byweight based on the dosage unit): magnesium stearate (0.01 to 0.3%),calcium stearate (0.01 to 0.3%), calcium behenate (0.01 to 0.3%), sodiumstearylfumarate (0.01 to 1.0%), lecithin (e.g. egg/soybean) (0.01 to0.5%), polyethylene glycol (0.01 to 1.0%), stearic acid, (0.01 to 1.0%),hydrogenated cottonseed oil (0.01 to 0.3%), hydrogenated castor oil(0.01 to 0.3%), talc (0.01 to 2.0%), rice starch (0.01 to 2.0%), calciumcarbonate (0.01 to 1.0%), titanium dioxide (0.01 to 2.0%), highlydisperse silica (0.01 to 0.1%), laked dyes (0.01 to 0.5%), iron oxidedyes (0.01 to 0.5%), silicones (0.01 to 0.5%), paraffins (0.01 to 0.5%),carnauba wax (0.01 to 0.5%), beeswax (0.01 to 0.5%), ethyl oleate (0.01to 0.3%), stearyl alcohol (0.01 to 1.0%), surfactants, e.g. Cremophor EL(0.01 to 0.3%).

Liquid agents which modify the surface properties, such as polyethyleneglycols, silicones, paraffins, ethyl oleate, can be applied directly bydipping the preformed plastic mixture or the mold surfaces or bybrushing or spraying on. Substances which can be dissolved in a solvent,such as lecithin in water or alcohol, polyethylene glycol (with amolecular weight of more than 1000) in water, surfactants in water or,for example, alcohol, are applied as solution as described above.Substances which cannot be dissolved or can be dissolved onlyinadequately in a solvent, such as magnesium stearate, talc or waxes,are applied as suspension or dispersion in a solvent, where appropriatein combination with liquid or dissolved agents which modify the surfaceproperties, as described above. Substances which cannot be dissolved orcan be dissolved only inadequately and, in addition, are in veryfine-particle form (particle sizes of less than about 50 μm), can besprayed on through an air spraying device (two-component nozzles). Thesesubstances include, for example, magnesium stearate, calcium carbonate,sodium stearylfumarate, titanium dioxide and laked dyes. The spraying oncan take place, depending on the required application rate, in the dry(without further ancillary substance) or suspended in a carrier such aswater or polyethylene glycol, or in a rapidly evaporating solvent, e.g.acetone. The methods mentioned are preferably suitable for providing anagent which modifies the surface properties on an extruded productshortly before the calendering or on the mold surfaces which come intocontact with the plastic mixture.

The process according to the invention has the following advantages: thesolid dosage forms obtained according to the invention contain the agentwhich modifies the surface properties only on their surface, notthroughout the composition. This makes it possible to reduceconsiderably the amount of agents which modify the surface properties.This in turn allows the dosage forms to be made considerably smaller forthe same amount of active ingredient, which leads to a larger yield perbatch and makes the production process more cost-effective. The agentswhich modify the surface properties used in the process according to theinvention may also be those which are incompatible with one or moreconstituents of the tablet composition, because the agent which modifiesthe surface properties is substantially separated in space from thematrix of the dosage forms. It is possible to produce a stock batch of apharmaceutical mixture which can be provided as required with differentagents which modify the surface properties. Particularly on use ofagents which modify the surface properties and have a lubricant actionthere is a reduction in the problems connected with the tackiness of theplastic mixture. The shaped dosage forms need not have completely cooledwhen leaving the mold, and the speed of manufacture can be increasedwithout any disadvantage.

EXAMPLE

Extruded tablets of a vitamin B complex of the following compositionwere produced:

Vitamin B complex 13.32% Klucel EF 20.00% Isomalt 66.68%

Lenticular tablets with a weight of 250.0 mg were produced.

For the production, the vitamin B complex, Klucel EF and isomalt weremixed in a container mixer for about 20 min and then extruded. The setparameters for the extrusion and the calender temperature in tests T 1to T 3 are indicated below:

Parameter T 1 T 2 T 3 Melt flow rate [kg/h]  25  25  25 Screw speed[rpm] 130 130 130 Vacuum [mbar] 150 105 105 Feed section temp. [° C.] 23  23  23 Section 1 temp. [° C.]  80  80  80 Section 2 temp. [° C.]100 100 100 Section 3 temp. [° C.] 110 110 110 Section 4 temp. [° C.]110 110 110 Head temp. [° C.] 120 120 120 Die temp. [° C.] 120 120 125Calender temp. [° C.]  18  12  30

It was not possible to detach the tablets from the molding rolls becauseof strong adhesion. In another test (T 4), the procedure of test T 3 wasused but a dish filled with ethyl oleate was placed beneath each of thetwo calender rolls. The depth of immersion of the rolls in the liquidwas such that all the indentations on the lowest point of the rolls werewetted (minimum immersion depth). The tablet composition described abovecould be removed from the molding rolls wetted in this way virtuallywithout adhesion.

The increase in weight of the tablets due to the ethyl oleate, which wasdetermined by weighing, was about 0.1% in this case.

In further tests, combinations of agents which modify the surfaceproperties were employed, such as a suspension of 2% magnesium stearatein a mixture of 10% polyethylene glycol 600 in water. In this case,about 0.15% polyethylene glycol and about 0.03% magnesium stearateremained on the extruded tablets.

We claim:
 1. A process for producing solid dosage forms by forming aplastic mixture of 10 to 99.9% by weight of at least one polymericbinder, 0.1 to 90% by weight of at least one active ingredient and,where appropriate, conventional additives, and shaping the solvent-freeplastic mixture to the solid dosage forms using a mold, wherein an agentwhich modifies the surface properties is applied in finely divided formto the surface of the plastic mixture during the shaping, wherein theagent which modifies the surface properties is initially applied infinely divided form to the surfaces of the mold which come into contactwith the plastic mixture to be shaped, and every contact of the surfacesof the mold with the plastic mixture is followed by a new application ofthe agent which modifies the surface properties.
 2. A process as claimedin claim 1, wherein the mold comprises two counterrotating molding rollsof which at least one has depressions to receive and shape the plasticmixture.
 3. A process as claimed in claim 2, wherein application of theagent which modifies the surface properties to the molding rolls takesplace by the underside of the rolls passing through a bath, or by theagent being sprayed on or applied using brushes.
 4. A process as claimedin claim 1, wherein the agent which modifies the surface properties is asurfactant.
 5. A process as claimed in claim 1, wherein the agent whichmodifies the surface properties is a lipophilic compound which isselected from glycerides, waxes, fatty acids, fatty alcohols, paraffins,silicones and phosphatides.
 6. A process as claimed in claim 1, whereinthe agent which modifies the surface properties is an antioxidant.
 7. Aprocess as claimed in claim 1, wherein the agent which modifies thesurface properties is a coloring agent.
 8. A process as claimed in claim1, wherein the agent which modifies the surface properties is an agentwith antistatic effect and/or lubricant effect.
 9. A process as claimedin claim 1, wherein the agent which modifies the surface propertiescomprises about 0.01 to about 1.0% by weight, based on the total weightof the resulting solid dosage form.